Aaron Koenig, MD, Sage Therapeutics, Cambridge, MA, introduces positive allosteric modulation of the NMDA receptor as a novel therapeutic approach for the treatment of cognitive impairment in Huntington’s disease (HD). Several lines of evidence implicate NMDA system dysfunction in HD, as well as numerous other neurological and neuropsychiatric disorders. For example, levels of endogenous steroid 24(S)-hydroxycholesterol, a potent positive modulator of NMDAR function, have been shown to be reduced in patients with HD, with levels correlating with cognitive symptom severity. SAGE-718 is an oral, small molecule derivative of 24(S)-hydroxycholesterol, acting as a positive allosteric modulator of the NMDA receptor. It is hypothesized that restoring normal NMDA tone with SAGE-718 may have the potential to improve cognitive symptoms in HD. In studies to date, short term treatment with SAGE-718 has been associated with improved cognitive performance, particularly in the domain of executive functioning. SAGE-718 will now be investigated in a Phase II program to assess its effect on cognitive performance and functioning in patients with HD. The agent is also being explored in Alzheimer’s disease and Parkinson’s disease. This interview took place during the European Huntington’s Disease Network 2022 Plenary Meeting.
These works are owned by Magdalen Medical Publishing (MMP) and are protected by copyright laws and treaties around the world. All rights are reserved.
Transcript (edited for clarity)
SAGE-718 is an oral investigational drug. It works by modulating a receptor in the brain called the NMDA receptor, and it modulates that receptor through positive allosteric modulation. In Huntington’s disease and also a number of different neurodegenerative diseases, we see changes in NMDA functioning. And in Huntington’s in particular, we see that changes in this functioning correlate or track with changes in cognition...
SAGE-718 is an oral investigational drug. It works by modulating a receptor in the brain called the NMDA receptor, and it modulates that receptor through positive allosteric modulation. In Huntington’s disease and also a number of different neurodegenerative diseases, we see changes in NMDA functioning. And in Huntington’s in particular, we see that changes in this functioning correlate or track with changes in cognition. And so the idea with SAGE-718 is perhaps that by restoring aberrant or abnormal NMDA tone, you may be actually able to improve cognitive impairment early in Huntington’s and therefore have some meaningful effects for patients.
There is a lot of data to support this therapeutic hypothesis, and that includes both preclinical translational as well as clinical data. So on the translational side, one of the benefits of working in the Huntington’s space is that there are very well-established databases of patient data, patients who are followed for a number of years non-interventionally. One of those databases is the TRACK-HD sample that we actually had the opportunity to work with. What we found in that sample was that patients early in Huntington’s disease have lower levels of an endogenous or naturally occurring modulator of the NMDA receptor called 24S-hydroxycholesterol, and actually that these changes or these lower levels were correlated with changes in cognitive functioning over several years. So this was actually our reason to believe that there might be a linkage.
But then we took this a step further and actually treated a subset of patients with Huntington’s with SAGE-718, and were able to demonstrate an improvement in cognition. So we actually were able, over the course of two weeks, to improve scores on a number of tests, tests that actually measure aspects of cognition that are really important to everyday functioning, things like executive functioning and multitasking. And now what we announced at the conference is a comprehensive clinical trial program to further interrogate these effects.
•Aaron Koenig is an employee of Sage Therapeutics, Inc., and may hold stock and/or stock options.
•The PERSPECTIVE Program is sponsored by Sage Therapeutics, Inc.
•SAGE‐718 is an investigational drug and is not approved by the US Food and Drug Administration or any other regulatory agency as safe and effective for any use.